Targeted infusion of agents against Parkinson&#39;s disease

ABSTRACT

A system and method for treating Parkinson&#39;s disease by delivery of an agent within the brain. At least one image of a target region is acquired, and at least one magnetic resonance diffusion tensor imaging (MR-DTI) scan of the target region is acquired. A diffusion tensor is calculated from the at least one MR-DTI scan, and at least one of an agent distribution and an agent concentration from the images and the calculated diffusion tensor is calculated. Using at least one of the calculated diffusion tensor, the images, the calculated agent distribution, and the calculated agent concentration, the placement of a delivery instrument is planned to deliver the agent to the target region to achieve a desired agent concentration and/or agent distribution within the target region. Delivery of the agent can be coordinated with an applied electrical stimulation.

RELATED APPLICATION DATA

This application claims priority of U.S. Provisional Application No.60/619,129 filed on Oct. 15, 2004, which is incorporated herein byreference in its entirety.

FIELD OF THE INVENTION

The present invention relates generally to treating Parkinson's diseaseand, more particularly, to treating Parkinson's disease using a plannedtargeted delivery of therapeutic substances within the brain and aplanned placement of catheters within the brain.

BACKGROUND OF THE INVENTION

It is known that a lack of dopamine in the brain is associated withParkinson's disease. Dopamine is a chemical messenger (neurotransmitter)in the nervous system and is produced by neural cells directly in thebrain. It also is known that a specific molecule, GDNF (Glial-cell linederived neurotrophic factor), can reconstruct the capability of neuralcells to produce dopamine. GDNF is approximately a 20 kDa (kilodalton)glycosylated polypeptide and is known to be expressed by cells such asSeritoli cells, type 1 astrocytes, Schwann cells, neurons, pinealocytes,and skeletal muscle cells. The activity of GDNF as a survival factor fordopaminergic neurons suggests the potential use of GDNF in the treatmentof Parkinson's disease. Furthermore, GDNF promotes neuron survival,thereby slowing or stopping the progression of Parkinson's disease.

For the treatment of Parkinson's disease, GDNF can be delivered directlyto a target region, e.g., a posterior dorsal region of the Putamen, thesubthalamic nucleus (STN), etc., or cells expressing GDNF can bedelivered to the target region. Alternatively, viral vectors or pure DNAcan be a delivered locally to trigger GDNF production.

Methods of administering a drug or other material to a target part ofthe body are known in the art. For example, U.S. Pat. No. 6,026,316discloses a method for targeted drug delivery into a living patientusing magnetic resonance (MR) imaging. The method uses MR imaging totrack the location of drug delivery and estimate the rate of drugdelivery. More particularly, an MR-visible drug delivery device ispositioned at a target site to deliver a diagnostic or therapeutic drugsolution into the tissue. The spatial distribution kinetics of theinjected or infused drug agent are monitored quantitatively andnon-invasively using water proton directional diffusion MR imaging toestablish the efficacy of drug delivery at a targeted location.

U.S. Pat. No. 5,720,720 discloses a method of high-flow microinfusionthat provides convection-enhanced delivery of agents into the brain andother solid tissue structures. The method involves positioning the tipof an infusion catheter within a tissue structure, and supplying anagent through the catheter while maintaining a pressure gradient fromthe tip of the catheter during infusion. The method can be used todeliver various drugs, protein toxins, antibodies for treatment orimaging, proteins in enzyme replacement therapy, growth factors in thetreatment of various neurodegenerative disorders and viruses and genetherapy.

U.S. Pat. No. 5,735,814 discloses techniques for infusing drugs into thebrain to treat neurodegenerative disorders by an implantable pump andcatheter. The drugs are capable of altering the level of excitation ofneurons in the brain. A sensor is used to detect an attribute of thenervous system which reflects the hyperexcitation of the nerve cellsprojecting onto the degenerating nerve cells, and a microprocessoralgorithm analyzes the output from the sensor in order to regulate theamount of drug delivered to the brain.

Finally, U.S. Pat. No. 6,549,803 discloses the movement of material inan organism, such as a drug injected into a brain. The movement ismodeled by a uniformly structured field of static constants governingtransport by moving fluid and diffusion within the fluid. This supportsplanning of material introduction, (e.g., infusion, perfusion,retroperfusion, injections, etc.) to achieve a desired distribution ofthe material, continuing real-time feedback as to whether imagedmaterial is moving as planned and will be distributed as desired, andreal-time plan modification to improve results.

SUMMARY OF THE INVENTION

The above discussed prior art discloses techniques for infusing drugsinto the brain. The above prior art, however, does not disclose treatingParkinson's disease using a planned targeted delivery of a therapeuticsubstance to the brain. The present invention provides such a plannedtargeted delivery of a therapeutic substance and/or electric field tothe brain for the effective treatment of Parkinson's disease.Additionally, the effectiveness of the plan can be analyzed prior toperforming the treatment.

According to one aspect of the invention, there is provided a system andmethod for treating Parkinson's disease by delivery of an agent withinthe brain, wherein a target region of the brain can be identified and adelivery by infusion of the agent to the target region of the brain canbe planned. In an embodiment, the system and method further providescalculating a diffusion tensor of the target region, simulating anelectrical field of an electrode in the target region, and positioningthe electrode in the target region based on the diffusion tensor and thesimulated electrical field.

According to another aspect of the invention, there is provided a systemand method for treating Parkinson's disease, wherein at least one imageof a target region and at least one magnetic resonance diffusion tensorimaging (MR-DTI) scan of the target region may be acquired. A diffusiontensor from the at least one MR-DTI scan can be calculated, and at leastone of an agent distribution and an agent concentration can becalculated from the images and the calculated diffusion tensor. At leastone of the calculated diffusion tensor, the images, the calculated agentdistribution, and the calculated agent concentration can be used to planthe placement of a delivery instrument to deliver the agent to thetarget region to achieve a desired agent concentration and/or agentdistribution within the target region. In an embodiment, the system andmethod further provides simulating an electrical field of an electrodein the target region, and positioning the electrode in the target regionbased on the diffusion tensor and the simulated electrical field.

To the accomplishment of the foregoing and related ends, the invention,then, comprises the features hereinafter fully described andparticularly pointed out in the claims. The following description andthe annexed drawings set forth in detail certain illustrativeembodiments of the invention. These embodiments are indicative, however,of but a few of the various ways in which the principles of theinvention may be employed. Other objects, advantages and novel featuresof the invention will become apparent from the following detaileddescription of the invention when considered in conjunction with thedrawings.

The forgoing and other embodiments of the invention are hereinafterdiscussed with reference to the drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic diagram of a navigation system that can be used inconjunction with the present invention.

FIG. 2 is a flow diagram for predicting the concentration and/ordistribution of an agent in accordance with an embodiment of theinvention.

FIG. 3 is a block diagram of a computer system that can be used toimplement the method of the present invention.

DETAILED DESCRIPTION

In general, the term “infusion” is to be understood in accordance withthe invention as any administration of a liquid, vapor or solidsubstance and/or an infusing medium such as medicines, cells, genes,enzymes, proteins, antibodies, hormones, viruses or the like, e.g.,viral vectors and viruses such as Adeno-associated virus systems, intobody tissue, as opposed to systemic administration of an agent. Thesubstances are introduced directly into body tissue in order to surmounta barrier, such as the blood-brain barrier, for example. The substancescan be delivered within a relatively short period of time (e.g., via aninjection), or over a longer period of time (e.g., via a continuousand/or variable rate of delivery of the substance). Methods foradministering a substance are described in commonly owned U.S. patentapplication Ser. No. 10/075,108, the entire contents of which is herebyincorporated by reference.

In performing infusion of agents to treat Parkinson's disease, certainrecommended guidelines should be followed. For example, to minimizebackflow of the agent along a trajectory of a catheter, the diameter ofthe catheter lumen should be less than 1.5 millimeters. Alternatively, aspecially designed catheter that has varying diameters along its lengthcan be implemented, e.g., a tapered catheter. To keep the backflow lessthan 3 centimeters, the flow rate of the delivered agent should be lessthan about 7 micro liters per minute.

A method for targeted infusion of agents in the brain to treatParkinson's disease is provided. As used herein, an “agent” or “agents”to be infused includes GDNF, GDNF expressing cells, GDNF expressingviral vectors and Adeno-associated virus systems, and any other agentuseful for treating Parkinson's disease through targeted infusion.

Patient data and/or patient parameters of the brain are acquired and/orcalculated prior to administering the agents. Patient data and/orparameters relating to the brain can be obtained using known techniques,including, for example, magnetic resonance (e.g., dynamiccontrast-enhance magnetic resonance imaging, magnetic resonanceperfusion imaging) or nuclear spin resonance methods (MRI), computertomography (CT), positron emission tomography (PET), single photonemission computerized tomography (SPECT), biopsy, x-rays and/orultrasound. Additionally, other suitable methods that enable the spatialstructure of a body and/or a tissue structure (e.g., the brain) to bedetected and viewed can be used. In addition to the above imagingtechniques, patient parameters such as, for example, tissue density, thedistribution of tissue structures, and/or the blood flow through aparticular area of tissue, also can be obtained from known data oftypical specimens and/or measured using other accepted medicalprocedures. Such data can be stored in a database, for example.

Once the patient data has been obtained, mathematical models are appliedto the data to extract relevant information. Sources (catheters) andsinks (non-intact blood-brain barrier, outflow through sulcii, outflowfrom cortical surface, binding to cells, etc.) as well as individualanatomy and physiology and catheter positions are considered in modelingthe concentration and distribution of the agents. More specifically,data relating to diffusivity, pathways, nerve tracks, electricalconductivity, fluid conductivity, pressure, etc., are extracted from theimages and/or other measurements. Using the data, a calculation is madeof the possible distribution of the agents, the possible concentrationof the agents and/or the possible electrical fields in the targetregion. In performing the calculations, the extracted information isrelated to flow (transport mechanisms), efflux (permeability,blood-brain barrier), diffusion (transport mechanisms), conductivity andanatomical white/grey matter) information, and/or electricalconductivity. Furthermore, chemical, pharmaceutical and/or biologicalproperties of each agent can be used in the calculations, therebyincreasing the specificity of the calculations.

The calculations can be performed, for example, using a computer toexecute code that calculates the agent concentration, the agentdistribution and/or the electrical field based on known properties ofthe agent and/or the target region. The computer can provide the resultsof the calculations via a computer display, for example.

Additionally, a simulation of a distribution of an electricalstimulation field can be combined with the above calculations, wherebyinfluence of local agent administration can be modeled into thesimulation of the electrical field. The electrical stimulation field canbe introduced via the catheter and/or a stimulation probe, whereinstimulation electrodes and/or measurement electrodes are fixed to thecatheter and/or probe, for example. Once the concentration and/ordistribution of the agent is determined, and/or the simulation of theelectrical field is obtained, the data can be displayed or otherwisereported to medical personnel for evaluation. This can be performed, forexample, via a simulation presented on the computer display. Morespecifically, two-dimensional and/or three-dimensional images of thetarget region can be viewed on the computer display, and the expected orcalculated concentration and/or distribution of the agent and/or thesimulated electrical field can be shown on the images of the targetregion.

Should the results (e.g., the concentration and/or distribution of theagent, and/or the electrical field data) be unsatisfactory, i.e., theydo not meet established or otherwise desired criteria for the procedure,then the plan can be refined and re-evaluated until a satisfactory planis obtained. If, on the other hand, the results are satisfactory, thenthe plan can be saved and transferred to a navigation system forexecution of the plan.

Referring initially to FIG. 1, a medical navigation system 2 that can beused in conjunction with the present invention is illustrated.Navigation systems of various types are well known in the art andtherefore will not be discussed in detail herein. Briefly, and by way ofexample, pre-operative images and/or operative images of a patient 4 areprovided to a computer controller 6. The patient 4 is placed on anoperating table 8, and a reference star 10 or other suitable trackabledevice is rigidly fixed to an area of interest of the patient, e.g. thecranium. The reference star 10 can include passive and/or activeelements 10 a that are detectable by at least two cameras 12 or otherdetection apparatus. The cameras 12 ascertain the spatial position ofthe reference star 10 and, therefore, the spatial position of the areaof interest, and provide the spatial information to the computercontroller 6 via a wired or wireless communications link 14.

Prior to displaying the patient's pre-operative or operative images, thepatient 4 is registered into the navigation system 2. Registration isthe process of teaching the computer controller 6 the location of thearea of interest on the patient with respect to the reference star 10and correlating the patient location to previously obtained data. Thiscan be done, for example, by indicating to the computer controller 6 thelocation of several points on the patient 4 using an instrument 16, suchas a probe, for example, having active or passive elements 10 a thereon.Provided the computer controller 6 knows the geometry of the instrument16, the computer controller can ascertain the location of a tip 16 a ofthe instrument. By placing the tip 16 a of the instrument on severalpoints on the patient 4, the computer controller 6 can ascertain thespatial position of the area of interest with respect to the referencestar 10 and correlate the preoperative and/or operative images to thearea of interest, thereby completing registration. Once registered, thecomputer controller 6 displays the images on one or more displays 18 viaa video link 18 a. Those skilled in the art will appreciate that theregistration process can be performed in other ways.

As the patient 4 is moved on the table 8, the images displayed on thedisplay 18 also move so as to always show the images with the correctpositional relationship. Moreover, one or more instruments 16, such as acatheter, a probe, etc., also can be displayed on the display 18,provided the geometry of each instrument is known by the computercontroller 6. A known navigation system is VectorVision™, available fromBrainLAB AG, and described, for example, in U.S. Patent Publication No.2003/0225329, which is hereby incorporated by reference.

Referring now to FIG. 2, a flow diagram 50 illustrating a method inaccordance with an embodiment of the invention is provided. The flowdiagram includes a number of process blocks arranged in a particularorder. As should be appreciated, many alternatives and equivalents tothe illustrated steps may exist and such alternatives and equivalentsare intended to fall with the scope of the claims appended hereto.Alternatives may involve carrying out additional steps or actions notspecifically recited and/or shown, carrying out steps or actions in adifferent order from that recited and/or shown, and/or omitting recitedand/or shown steps. Alternatives also include carrying out steps oractions concurrently or with partial concurrence.

Beginning at step 52, the target region is determined and/or outlined.For example, it may be known through literature, experience or previousdiagnostic tests that a certain region of the brain is responsible forParkinson's disease, e.g., the posterial dorsal region of the Putamen.Thus, this region can be said to be the target region. Alternatively,the target region can be identified by measuring electrical activityfrom the cells in an area of interest. Cell types having the same amountor type of electrical activity can be classified as the same cell type.The same cell types can be grouped together and classified as the targetregion, as indicated in alternative steps 52 a-52 c.

For example, certain cell types may be known to exhibit a certain amountof electrical activity, while other cell types may exhibit differentamounts or different types of electrical activity. As used herein,electrical activity refers to at least one or more of an impedance, ashape of an electrical waveform, an amplitude of the electricalwaveform, a frequency of the electrical waveform, or other electricalproperties. By monitoring the electrical activity of the cells,different cell types belonging to different tissue regions or abnormalcells can be identified. Based on knowledge obtained from monitoringelectrical activity of different cells, a desired target region can beidentified and clearly delineated from surrounding cells or regions.

As was noted above, electrical activity can be monitored by placingmeasurement electrodes on a catheter or probe and inserting the probeinto or near the target region. The measurement electrodes detect theelectrical activity and, via a wired or wireless communication link,provide the electrical data to the computer controller 6. The computercontroller 6 can analyze the data and establish a pattern for the celltypes. Based on a predetermined criteria, e.g., the shape of thewaveform, the frequency of the waveform, the amplitude of the waveform,known electrical activity from various regions of the brain, etc., thecomputer controller 6 can distinguish between different cell types andidentify the target region.

Once the target region is determined and/or outlined, with or withoutthe above described procedures, an initial trajectory for a deliveryinstrument, e.g., a catheter, is planned (catheter planning), asindicated at step 54. The initial trajectory can be based on knowledgeand/or experience with a particular procedure, accepted practices bythose skilled in the art, recommendations by medical experts and/ormedical societies, or any other criteria accepted by those skilled inthe art. According to one embodiment, multiple catheters are used toensure coverage of the entire target area.

Next, at step 56 three-dimensional images of the target region areobtained using any one of several imaging techniques, e.g., MRI, CT,PET, SPECT, etc. The three dimensional images of the target region canbe automatically segmented so as to present internal or partial views ofthe target region as is conventional. According to one embodiment, highresolution MRI scans having at least 1 millimeter in-plane spatialresolutions are obtained of the target region. Additionally, furtherimages can be obtained relating to the anatomy and/or physiology of thepatient and/or the target region. The additional images can be obtainedusing the above mentioned imaging techniques. Such data can be used toidentify tissue density and blood flow through a particular area oftissue, for example.

Moving to step 58, MR-DTI scans are acquired of the target region. As isknown by those skilled in the art, MR-DTI uses water diffusion to obtainstructural information about the brain. MR-DTI can reveal properties ofthe brain that are not accessible through standard structural MRimaging. Using the MR-DTI scans, the diffusion tensor for the targetregion is calculated as indicated at step 60.

For example, a 3×3 matrix can represent the diffusion tensor. This maybe accomplished with six independent elements. It generally is agreed inthe art that at least three directions of the diffusion weightinggradient (which are independent of the preferred directional diffusion)should be sampled to generate trace images. These trace images are thesum of the diagonal elements of the diffusion tensor. Further, a minimumof 6 directions should be sampled for each voxel, if the full diffusiontensor is to be evaluated.

The MR signal of the scan depends on both the direction and magnitude ofa diffusion weighting gradient. Through combinations of the x, y, and zgradients, the MR signal can be sensitized to the component of diffusionin any arbitrary direction. The diffusion tensor can be calculated, forexample, by obtaining measurements with diffusion weighting gradients inat least six non-collinear directions (since the symmetric tensor itselfas six independent components) as well as with no diffusion weighting.In practice, many more directions may be measured, and a fittingprocedure can be used to calculate the six tensor components for eachvoxel.

According to one embodiment, MR-DTI imaging parameters utilize a matrixsize of 128², and more preferably a matrix size of 256². According toanother embodiment, the slice thickness of the images is below 3millimeters and gaps between slices preferably are avoided to allowproper three-dimensional reconstruction.

Based on the above acquired data, e.g., MRI, MR-DTI, diffusion tensor,etc., the agent distribution, the agent concentration and/or theelectrical field in the target region are calculated as indicated atstep 62. More specifically, data relating to diffusivity, pathways,nerve tracks, electrical conductivity, etc., are extracted from theimages and/or measurements. The extracted information then is related toflow (transport mechanisms), efflux (permeability, blood-brain barrier),diffusion (transport mechanisms), conductivity and anatomical(white/grey matter) information, and/or electrical conductivity topredict possible distribution of the agents, possible concentration ofthe agents and/or electrical fields in the target region.

For example, and as was noted above, the three dimensional images of thetarget region can be automatically segmented so as to present internalor partial views of the target region. Anatomical data can be segmentedinto clusters of similar anatomical and/or physiological properties suchas bone, tissue, tissue/vascular system and spinal cord/brain. Next,hydraulic properties and/or vascular or other permeability properties ofeach cluster can be determined from the obtained anatomical and/orphysiological data. Nerve fibers can be tracked by interpreting localvariations of diffusivity to determine pathways of nerves in the brainclusters. The determined nerve pathways also can be used to derive thetarget regions.

In making the above calculations, the blood-brain barrier disruption isassumed to be negligible, so efflux or influx from/to the vascularsystem of the target region can be neglected. Additionally, perfusion ordynamic T1 data acquisition is not necessary, although they may beapplied to determine local variations of vascular permeability, vascularinflux or vascular efflux from distinct regions of the target region.

Local variations in pore fraction can be derived from identificationand/or segmentation of gray and white matter structures applying knownvalues from the literature. Alternatively, multiple b-value MR-DTI scanscan be applied to estimate pore fraction or b0 or T2 images from MRIscans can be used to estimate pore fraction.

Chemical, pharmaceutical and/or biological properties of each agent alsocan be applied in the above calculations. More specifically, parametersof the agent that characterize the substance to be administered and/ordefine the physical, chemical and/or biological properties and/orelectrical properties of the agent can be used. The parameters canrelate to a molecular or particle size of the substance to beadministered, a rate of diffusion of the substance in a particular typeof tissue, a metabolism and/or interaction of the substance with tissuedue to metabolic processes, a diffusion coefficient known for thesubstance for the type of tissue to be treated, a preferred injectionpressure or pressure gradient, the influence of the substance to theelectrical properties of the tissue, a preferred concentration of thesubstance, and/or the quantity or rate of delivery. Such data can bestored and retrieved from a database residing on the computer controller6, for example.

It is noted that should the flow rate of the agent reach zero, thenthere is no convection, leaving only diffusion as the driver for thedistribution process. In such a case, the mathematical model may beadjusted to only use diffusion to calculate agent distribution andconcentration (e.g., a model based on the magnetic resonance diffusiontensor imaging (MR-DTI) data and anatomical/physiological data).

Moving to step 64, the acquired data (e.g., the image scans) and thecalculated data are combined and used to perform a simulation of theplanned infusion and/or a simulation of the expected electrical fielddistribution. The simulation also can be based on infusion with respectto the individual anatomical environment and/or to chemical and physicalproperties of the infused agent. Using a simulation, the agentconcentration, the agent distribution and/or the electrical fields inthe target region can be determined statistically and dynamically as afunction of time. Thus, it can be established prior to the actualprocedure whether the desired agent concentration, agent distributionand/or electrical field distribution will be achieved.

For example, and as was noted previously, the images of the targetregion can be viewed on a computer display and the calculated data,e.g., the expected agent concentration, the expected agent distribution,and the expected electrical field, can be included with and/orsuperimposed on the image scans. By accurately rendering the agentconcentration, the agent distribution and/or the electrical field in thetarget region on the actual images of the target region, medicalpersonnel can visually observe the results of the plan.

Medical personnel, depending on the outcome of the simulation, candetermine whether the results are satisfactory or whether furtherplanning is required, as indicated at step 66. Alternatively, thecomputer controller 6 can provide an indication as to whether theplanned infusion meets certain specified criteria and, subject toacceptance by medical personnel, the plan can be implemented. If theplan is acceptable, the plan is saved and executed by the navigationsystem 2, as indicated at step 70.

According to one embodiment, guidelines are presented to the medicalpersonnel during execution of the plan. For example, the guidelines maypresent information relating to recommended depths of the catheter orthe stimulation probe and/or to recommended geometric relationsregarding specific anatomical structures.

If the plan is not acceptable, then the plan is refined at step 68 andthe process moves back to step 62. The plan can be refined, for example,by changing one or more of the planned depth of the delivery instrumentinto the target region, the planned entry angle of the deliveryinstrument, the flow rate of the agent, the amount of agent introducedin the target region, or any other parameter related to delivery of theagent or the agent itself. According to one embodiment, the computercontroller 6 presents alternate catheter positions and/or alternate flowrates. The alternate flow rates, for example, can be based on catheterposition, the specifics of the anatomy and physiology of the targetregion, and/or on measured electrical activity within the cells, asindicated in steps 68 a and 68 b. The computer controller can beprovided with an initial plan and the computer controller 6, using theinitial plan, can determine a location and/or delivery of the agent thatsatisfies a predetermined criteria.

Refinements also can be based on simulations of an electrical fieldgenerated by the electrode. More particularly, proper positioning of theelectrode can be based on a simulation of the electrical field of theelectrode and the calculated diffusion tensor. The simulated electricalfield also can be combined with the calculated agent concentrationand/or the calculated agent distribution, whereby the influence of theagent on the electrical properties of the tissue of the target regioncan be taken into account to model the distribution the electricalfield, or vice versa. The results of the electrical field simulation, incombination with the simulation of the agent distribution and/or agentconcentration, can be combined for planning and/or refining the plannedimplantation of the electrode and/or the delivery catheter.

Additionally, the electrical stimulation and/or the intensity of theelectrical stimulation in combination with the delivery/release of theagent can be triggered and/or adjusted. For example, thedelivery/release of the agent can be coordinated with the application ofan electrical stimulation applied to the target region. Alternatively,the delivery/release of the agent can be conditioned on a measured orapplied intensity of the electrical stimulation in the target region,e.g., the agent is delivered when the stimulation is above, below orequal to a predetermined threshold.

The above described method can be implemented using the computercontroller 6 of the navigation system 2 (described in more detailbelow), or another computer not associated with the navigation system.Additionally, it is noted that the invention can be implemented to befully automatic, e.g., using data and/or parameters stored in adatabase, semi-automatic, e.g., selections displayed on a menu are madeby an operator, or manual, e.g., values are input by an operator.

Moving to FIG. 3, a computer controller 6 for executing a computerprogram in accordance with the present invention is illustrated. Thecomputer controller 6 includes a computer 72 for processing data, and adisplay 74 for viewing system information. The technology used in thedisplay is not critical and may be any type currently available, such asa flat panel liquid crystal display (LCD) or a cathode ray tube (CRT)display, or any display subsequently developed. A keyboard 76 andpointing device 78 may be used for data entry, data display, screennavigation, etc. The keyboard 76 and pointing device 78 may be separatefrom the computer 72 or they may be integral to it. A computer mouse orother device that points to or otherwise identifies a location, action,etc., e.g., by a point and click method or some other method, areexamples of a pointing device. Alternatively, a touch screen (not shown)may be used in place of the keyboard 76 and pointing device 78. A touchscreen is well known by those skilled in the art and will not bedescribed in detail herein. Briefly, a touch screen implements a thintransparent membrane over the viewing area of the display 74. Touchingthe viewing area sends a signal to the computer 72 indicative of thelocation touched on the screen. The computer 72 may equate the signal ina manner equivalent to a pointing device and act accordingly. Forexample, an object on the display 74 may be designated in software ashaving a particular function (e.g., view a different screen). Touchingthe object may have the same effect as directing the pointing device 78over the object and selecting the object with the pointing device, e.g.,by clicking a mouse. Touch screens may be beneficial when the availablespace for a keyboard 76 and/or a pointing device 78 is limited.

Included in the computer 72 is a storage medium 80 for storinginformation, such as application data, screen information, programs,etc. The storage medium 80 may be a hard drive, for example. A processor82, such as an AMD Athlon 64™ processor or an Intel Pentium IV®processor, combined with a memory 84 and the storage medium 80 executeprograms to perform various functions, such as data entry, numericalcalculations, screen display, system setup, etc. A network interfacecard (NIC) 86 allows the computer 72 to communicate with devicesexternal to the system 6.

The actual code for performing the functions described herein can bereadily programmed by a person having ordinary skill in the art ofcomputer programming in any of a number of conventional programminglanguages based on the disclosure herein. Consequently, further detailas to the particular code itself has been omitted for sake of brevity.

The above described methodology can also have application in treatingother diseases through the use of a corresponding agent havingtherapeutic properties for the particular disease. Accordingly, thepresent invention provides in more general terms a method for treating adisease by delivery of an agent within the brain (or other bodylocation). The method includes identifying a target region of the brain(or other body location), and planning a delivery by infusion of theagent to the target region of the brain (or other body location). Thepresent invention also provides a method for treating a disease bydelivery of an agent within the brain (or other body location), whereinat least one image of a target region and at least one magneticresonance diffusion tensor imaging (MR-DTI) scan of the target regionare acquired. A diffusion tensor is calculated from the at least oneMR-DTI scan, and at least one of an agent distribution and an agentconcentration is calculated from the images and the calculated diffusiontensor. Using at least one of the calculated diffusion tensor, theimages, the calculated agent distribution, and the calculated agentconcentration, the placement of a delivery instrument is planned todeliver the agent to the target region to achieve a desired agentconcentration and/or agent distribution within the target region.

As will be appreciated, the various computer codes for carrying our theprocesses herein described can be embodied in computer-readable media.In addition, the various methods and apparatus herein described can be,individually or collectively, supplemented with one or more of thevarious methods and apparatus described in U.S. patent application Ser.Nos. 10/464,809, 10/661,827, 11/115,093, 10/753,979, 10/771,545,10/442,989 and 09/745,039, and in U.S. Pat. Nos. 6,464,662, 6,549,803and 6,572,579, except to which such methods and apparatus areinconsistent with the herein described methods and apparatus. All of theaforesaid patent applications and patents are herein incorporated byreference in their entireties.

Although the invention has been shown and described with respect to acertain preferred embodiment or embodiments, it is obvious thatequivalent alterations and modifications will occur to others skilled inthe art upon the reading and understanding of this specification and theannexed drawings. In particular regard to the various functionsperformed by the above described elements (components, assemblies,devices, compositions, etc.), the terms (including a reference to a“means”) used to describe such elements are intended to correspond,unless otherwise indicated, to any element which performs the specifiedfunction of the described element (i.e., that is functionallyequivalent), even though not structurally equivalent to the disclosedstructure which performs the function in the herein illustratedexemplary embodiment or embodiments of the invention. In addition, whilea particular feature of the invention may have been described above withrespect to only one or more of several illustrated embodiments, suchfeature may be combined with one or more other features of the otherembodiments, as may be desired and advantageous for any given orparticular application.

1. A method for treating Parkinson's disease by delivery of an agentwithin the brain, the method comprising the steps of: identifying atarget region of the brain; and planning a delivery by infusion of theagent to the target region of the brain.
 2. The method of claim 1,further comprising the step of delivering the agent to the target regionof the brain based on the plan.
 3. The method of claim 2, furthercomprising the step of using an agent selected from the group consistingof GDNF, GDNF expressing cells, GDNF expressing viral vectors andAdeno-associated virus systems.
 4. The method of claim 2, furthercomprising the step of adjusting a flow rate of the agent based on anactual catheter placement compared to the planned catheter placement. 5.The method of claim 2, further comprising the steps of: calculating adiffusion tensor of the target region; simulating an electrical field ofan electrode in the target region; and positioning the electrode in thetarget region based on the diffusion tensor and the simulated electricalfield.
 6. The method of claim 5, further comprising the steps of:simulating at least one of a concentration of the agent in the targetregion and a distribution of the agent in the target region; andrefining the planned catheter and/or electrode placement based on thesimulated agent distribution, the simulated agent concentration and/orthe simulated electrical field.
 7. The method of claim 5, wherein thesteps of calculating the diffusion tensor and/or simulating theelectrical field includes the step of using at least one of chemical,pharmaceutical, biological and electrical properties of the agent toperform the respective calculation and/or simulation.
 8. The method ofclaim 2, further comprising the step of coordinating the delivery of theagent with an applied electrical stimulation signal.
 9. The method ofclaim 2, further comprising the step of delivering the agent uponmeasuring and/or applying an electrical stimulation signal in the targetregion that is greater than, equal to, or less than a predeterminedthreshold level.
 10. The method of claim 1, wherein the step ofidentifying the target region of the brain includes the steps of:measuring electrical activity from cells within a region of the brain;identifying different cell types based on the measured electricalactivity; and identifying the target region to include cell types thatexhibit substantially the same electrical activity.
 11. The method ofclaim 1, wherein the step of planning the delivery of the agent includesthe steps of: acquiring at least one three-dimensional image of thetarget region; acquiring at least one magnetic resonance diffusiontensor imaging (MR-DTI) scan of the target region; calculating adiffusion tensor from the MR-DTI scan; and calculating at least one of aconcentration of the agent in the target region and a distribution ofthe agent in the target region.
 12. The method of claim 11, wherein thestep of acquiring at least one three-dimensional image of the targetregion includes the step of obtaining image scans that have at leastabout 1 mm in-plane spatial resolution.
 13. The method of claim 11,wherein the step of calculating at least one of the concentration of theagent and the distribution of the agent includes the step of simulatingthe concentration and/or distribution of the agent in the target region.14. The method of claim 13, further comprising the step of providingalternate catheter positions to provide simulation results that meet aspecified criteria.
 15. The method of claim 1, further comprising thestep of providing guidelines for catheter placement.
 16. The method ofclaim 1, wherein the step of delivering the agent to the target regionincludes the step of delivering the agent to the target region at aspecified flow rate.
 17. The method of claim 16, further comprising thestep of limiting the flow rate to be less than about seven micro-litersper minute.
 18. The method of claim 16, further comprising the step oflimiting the flow rate such that a back flow of the agent is less thanabout three centimeters from a delivery point of the agent.
 19. A methodfor treating Parkinson's disease by delivery of an agent within thebrain, the method comprising the steps of: acquiring at least one imageof a target region; acquiring at least one magnetic resonance diffusiontensor imaging (MR-DTI) scan of the target region; calculating adiffusion tensor from the at least one MR-DTI scan; calculating at leastone of an agent distribution and an agent concentration from the imagesand the calculated diffusion tensor; and using at least one of thecalculated diffusion tensor, the images, the calculated agentdistribution, and the calculated agent concentration to plan theplacement of a delivery instrument to deliver the agent to the targetregion to achieve a desired agent concentration and/or agentdistribution within the target region.
 20. The method of claim 19,further comprising the steps of: simulating an electrical field of anelectrode in the target region; and positioning the electrode in thetarget region based on the diffusion tensor and the simulated electricalfield.
 21. The method of claim 20, further comprising the steps ofsimulating at least one of a concentration of the agent in the targetregion and a distribution of the agent in the target region; andrefining the planned catheter placement based on the simulated agentdistribution, the simulated agent concentration and/or the simulatedelectrical field.
 22. The method of claim 19, further comprising thestep of coordinating the delivery of the agent with an appliedelectrical stimulation signal.
 23. The method of claim 19, furthercomprising the steps of: acquiring data relating to individual anatomyand/or physiology of the patient; and using at least one of the anatomydata, the physiology data, the image scans, the MR-DTI scan, thecalculated diffusion tensor, the calculated agent concentration and thecalculated agent distribution to perform a simulation of the agentconcentration and/or the agent distribution.
 23. A program embodied in acomputer-readable medium for treating Parkinson's disease by deliveringan agent within the brain, comprising: code that identifies a targetregion of the brain; and code that plans a delivery by infusion of theagent to the target region of the brain.
 24. A system for treatingParkinson's disease by delivering an agent within the brain, comprising:a processor circuit having a processor and a memory; a treatmentsub-system stored in the memory and executable by the processor, thetreatment sub-system comprising: logic that identifies a target regionof the brain; and logic that plans a delivery by infusion of the agentto the target region of the brain.